The present invention relates to the synthesis of carbapenem side chains, and in particular, to side chains or portions thereof containing a pyrrolidine group, which is bonded to the carbapenem nucleus through a thioether linkage. Typically, the pyrrolidine is a portion of the side chain, and is substituted at the two position with any of a variety of substituents.
Conventionally, these intermediate compounds are prepared from a 4-hydroxyproline derivative of the formula: ##STR4## Such synthetic schemes typically require the extensive use of protecting groups.
Similarly, a method of converting trans-4-hydroxy-L-proline to a thiolactone of the formula: ##STR5## has been described. However, this thiolactone is unsuitably protected for large scale synthesis of carbapenem antibiotics.
EP 551 993 Al published on Jul. 21, 1993 relates to a synthesis which utilizes active esterifying agents and base, followed by treatment with hydrogen sulfide and base.
The present invention is an improvement over these other processes, utilizing an activating agent, namely, diphenylphosphinic chloride, which surprisingly improves the results which are achieved when commercial quantities are synthesized.